SCP2 – Sterol Carrier Protein 2 Deficiency

SCP2 encodes peroxisomal sterol carrier protein X (SCPx), essential for branched‐chain fatty acid β‐oxidation. Biallelic loss‐of‐function SCP2 variants underlie sterol carrier protein 2 deficiency (MONDO:0013391), presenting with leukencephalopathy, dystonia, torticollis, nystagmus, hyposmia, and azoospermia in three reported patients (PMID:16685654; PMID:37905191). Variants include homozygous frameshift c.1170dup (p.Asn391Ter) and a splice‐site c.674+1G>C resulting in exon skipping.

Patient‐derived fibroblasts show absent SCPx protein and deficient thiolase activity (PMID:16685654). Structure–function analyses of recombinant SCP2 highlight critical residues (e.g., Asn104, Asp70) for lipid transfer activity (PMID:8300590). Together, existing genetic and functional data support a Limited ClinGen association due to small patient number and lack of segregation. Continued case ascertainment will be needed to achieve higher evidence tier. Key take-home: SCP2 homozygous LOF variants cause a consistent biochemical and neuro-metabolic phenotype useful for molecular diagnosis.

References

• American Journal of Human Genetics • 2006 • Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy. PMID:16685654
• Frontiers in Neurology • 2023 • Case report: Episodic psychosis caused by a novel SCP2 splicing mutation. PMID:37905191
• The Journal of Biological Chemistry • 1994 • Structure-activity studies of human sterol carrier protein 2. PMID:8300590

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